The aim of this research is to understand how skeletal muscle protein metabolism is regulated in insulin-dependent diabetes mellitus (IDDM) in response to physical exercise. The goal is to improve our understanding of the role of optimal insulin replacement during and following exercise to enable IDDM subjects to exercise appropriately and for maximal clinical benefit. This is based on two novel observations made during my NIH Clinical Investigator Award: 1) Following exercise, whole-body protein synthesis is increased, but protein synthesis in nonexercised muscle is decreased. This demonstrated for the first time that the effects of prior exercise on muscle protein metabolism are regional, and has led us to devise protocols that will directly determine in vivo rates of skeletal muscle protein synthesis (see FMPS, below); 2) Insulinopenic basal state, demonstrated the normal decrease in net protein catabolism following exercise. This unexpected finding led us to speculate that primary alterations in hormone concentrations in IDDM which increase protein catabolism may be counterbalanced by secondary effects to increase substrate availability after exercise which limit protein catabolism. Whole-body protein synthesis, degradation and leucine oxidation rates will be estimated from steady-state plasma alpha-[1-13C]-KIC enrichments during L-[1-13C]-leucine infusion. Regional protein synthesis and degradation will be measured from dilution of L-[ring-2H5] phenylalanine and phenylalanine balance across the leg during L-[ring-2H5]-PHE infusion. Direct estimates of fractional mixed skeletal muscle protein synthesis rates (FMPS) will be made from muscle biopsies of vastus lateralis skeletal muscle during L-[1-13C]-LEU infusions. These studies have great clinical relevance for IDDM subjects who use exercise as an important component of their therapeutic regimen. Hopefully, improved understanding of the role of optimal insulin replacement in normalizing protein metabolism will enable IDDM subjects to achieve maximal clinical benefit from their physical training programs.